More Data Integrity Warning Letters Issued To Sites OUS

December 25, 2016

This week FDA posted two warning letters to sites outside the US with significant data integrity deficiencies. One was issued to Teva Pharmaceuticals Private Limited Co. located in Godollo, Hungary, and the second was issued to Interpharm Praha A.S. located in the Modrany, Czech Republic. This continues the trend from FY2015 where ~ 80% of warning letters issued to drug firms outside the US include deficiencies in data management and data integrity. Trends of warning letters associated with data management and data integrity for FY2015 was addressed in a previous blog entry; I will publish the data for FY2016 here in a couple of weeks. The two warning letters addressed here begin the FY2017 collection and are addressed below:

Teva Pharmaceutical Works Private Limited Co (Godollo, Hungary) received a warning letter on October 13, 2016 based on the outcome of an inspection ending January 29, 2016. The 12-page form 483 is available for purchase at the FDAzilla store. Justin Boyd was one of the two investigators. As a reminder, an import alert was put in place on May 27, 2016. The warning letter identifies seven deficiencies and encourages the firm to have their consultant assist in their remediation and specifically mentions ‘Your consultant should provide a thorough assessment of your entire operation to identify contamination hazards, assist in remediation of sterility assurance in your facility, improve your quality system, and certify readiness [presumably for re-inspection].’ FDA encourages the firm to read the Aseptic Processing Guidance, and provides a detailed list of ‘data integrity remediation’ requirements that must be met. Deficiencies identified in the warning letter are associated with aseptic processing of sterile drug product and failures in data management / data integrity. Deficiencies include but are not limited to:

The firm did not adequately investigate media fill and sterility test failures. For example, the organisms found in contaminated media fill vials were not identified.

Multiple sterility test positive results were invalidated. FDA lists five activities that TEVA must perform and submit to FDA as part of remediation of the first deficiency in the warning letter.

Numerous examples of ‘poor aseptic behavior’ were identified, and FDA identifies additional information they must provide beyond their response to the form 483.

After a mechanical failure during a media fill the firm stops the run and invalidated the fill without adequate justification. The vials filled before the mishap were not incubated. Complicating this, the firm indicated that if this was a commercial run ‘…it would have released a commercial batch as a sub-lot under these circumstances.’ FDA identifies additional information the firm must provide to supplement what was an inadequate response to the form-483.

Operators performing activities in a Grade A area (open RABS and under laminar flow) were held to Grade B personnel monitoring alert and action limits.

Sterility test method used is not suitable for purpose because it failed to meet acceptance criteria when a positive control sample did not exhibit growth.

Colony counts for environmental and personnel monitoring did not match the data in the official records.

Interpharm Praha A.S. (Modrany, Czech Republic) received a warning letter on October 18, 2016 based on the outcome of an inspection ending October 16, 2015. The firm makes both APIs and finished dosage form and the warning letter addresses both. The warning letter focuses entirely on the lack of data integrity, and includes the coommon boilerplate set of detailed ‘data integrity remediation’ requirements that the firm must complete. The firm has not yet been placed on import alert. Deficiencies include but are not limited to:

API:

The firm had inadequate controls in place to prevent changes to electronic laboratory data. Further, the firm did not have a procedure to identify the requirements and restrict user access to the system. FDA describes ‘…we reviewed an audit trail from your Empower-2 system that stored 8,906 entries. Of these, well over half indicated some form of data deletion or manipulation, including at least 1,441 instances of deleted results, at least 3,643 instances of manual integration, and at least 194 instances of altered running sample sets.’ Thus, the Quality unit was not provided complete data to review for lot release decision making.

Analysts could modify chromatographic sequences and delete results without justification. At issue is the practice of manual integration where the investigators found ‘discrepancies in peak integrations, including inconsistent integrations, and peaks that were not integrated at all.’ Again, the Quality Unit did not have complete data for lot release decision making.

Analysts can modify or delete chromatographic results without adequate justification. Further manual integration was employed without the appropriate controls.

As with the API deficiencies, the Quality Unit did not have complete data for lot release decision making.

For both the API and drug product, the issue of manual integration is cited as a deficiency. It seems that this practice was so prevalent to suggest that the methods were not capable and that the reason for the frequent need for manual integration was not justified and/or clearly described in a procedure so that it was performed consistently.

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